parenteral drug delivery market trends...(irinotecan hydrochloride) formulation may realize promise...

Parenteral Drug Delivery Market Trends Kurt R. Sedo

Vice President, Operations PharmaCircle LLC

Sunny Isles Beach, FL

Parenteral Drug Delivery Market Trends

• Pipeline/Products Overview • Device Based Technology Trends

– Autoinjectors, pens, prefilled syringes, patch pumps…

• Formulation Based Technology Trends – Targeted Delivery, Drug Conjugates, Injectable Depot

• Other Technologies – Concentrated/Viscous, Stability, Injection Site Absorption Enhancers

• Key Approvals in Last 5 years • Drug Delivery

– Technologies, Deals, Analysis

• Venture Capital Investments • Conclusions

Overview: Innovator Products and Pipeline

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Route: Marketed vs Pipeline

Marketed

Pipeline

DD 38% Non-DD

62%

Marketed Products

DD 37%

Non-DD 63%

Pipeline Programs

Drug Delivery Pipeline Analysis

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DD Pipeline by Phase/Route

Phase 3

Phase 2

Phase 1

Preclinical

Research

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DD Pipeline Moved to Clinic 2017 - 2018

2017

2018

Trends: 2017 Innovator Approvals

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70

2017 Innovator Approvals by Route

FDA

EMA

Trends: 2017 Innovator Approvals

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70

Injection Injection Solution Injection Lyophilized Powder for

Solution

Injection Lyophilized Powder for Suspension

Injection Suspension

Injection Emulsion

2017 Innovator Approvals Injection Dosage Forms

FDA

EMA

Key Product Sales: 2003, 2010, 2017

Blue highlight cells are injectable. Blue italics have injectable formulation available in franchise in that year.

Overview/Trends: Injectables

• Injectables Taking Over Pipeline • Devices, Devices, Devices…

– Multiple device strategies incorporated into first approvals (e.g. Repatha, Aimovig)

• Delivery of High Volume and/or Viscous Biologics

• Trending Formulation Approaches – Biologic Formulation Stabilization – Controlled Release SC/IM (e.g. Depot) – Controlled Release IV (e.g. PEG, Fc) – Targeted (ADC, Nanoparticles) – Nucleic Acid Delivery – Cell Therapy – Local Delivery

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100 120 140 160 180

Injection Device Approvals 2012-2018

Injectable Marketed Product Analysis

small molecule

64%

protein 17%

peptide 7%

antibody 5%

carbohydrate 5%

Other 2%

Marketed Injectables by Molecule Type

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Marketed Injectables by Indication

Injectable Marketed Product Analysis

Infusion IV 28%

Injectable IM 22%

Injectable SC 20%

Injectable IV 20%

Intradermal 2%

Intraarticular 1%

Infusion SC 1%

Other 6%

Marketed Injectables by Route

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8000

Marketed Injectables by DD Category

Injectable Pipeline Analysis

antibody 32%

small molecule

18% protein 13%

cell based 13%

peptide 10%

gene 7%

oligo 2%

RNA 3%

other 2%

Injectable Pipeline by Molecule Type

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3000

4000

5000

6000

Injectable Pipeline by Indication

Infusion IV 34%

Injectable SC 22%

Injectable IV 17%

Injectable IM 10%

Intradermal 4%

Intravitreal 2%

Other 11%

Injectable Pipeline by Route

Injectable Pipeline Analysis

0 1000 2000 3000 4000 5000 6000 7000 8000 9000

Injectable Pipeline by DD Category

Injectable Pipeline/Product Analysis

Solution 59%

Suspension 16%

Lyo/Powder 19%

Emulsion 2%

Other 4%

Injectable Pipeline Dosage Form

Solution 66%

Lyo/Powder 23%

Suspension 8%

Emulsion 1%

Other 2%

Injectable Marketed Dosage Form

Evolution of Device Development

1998 2004 2017 2006

Enbrel

Past: Devices as LCM Strategy

2015

Present: Multiple Devices at Launch and Compressed LCM

2016

Repatha

Injectable Nanoparticles

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400

Injectable Nanoparticles by Phase

Marketed

Approved

Registration

Phase 3

Phase 2

Phase 1

Preclinical

Research

Drug Conjugates

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400

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800

Drug Conjugates by Phase

Marketed

Approved

Registration

Phase 3

Phase 2

Phase 1

Preclinical

Research

Injectable Depot

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250

Injectable Depot Products/Pipeline

Marketed

Reg/Approved

Phase 3

Phase 2

Phase 1

Research/Pre

Injectable Depot

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Injectable Depot Indications

LCM Case Study: Risperidone

Product Approval (US)

Risperdal Oral Tablet

1993

Risperdal Oral Solution

1996

Risperdal M-Tab ODT

2003

Risperdal Consta Injectable (1 x 2 weeks)

2003 0

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rld

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$

LCM Risperdal Franchise

Risperdal Total

Risperdal Injectable

Risperdal Oral

Risperdal Consta utilizes MedisorbTM PLGA depot technology

LCM Case Study: Paliperidone

Product Approval (US)

Invega ER Oral Tablet

2006

Invega Sustenna Injectable (1 x month)

2009

Invega Trinza Injectable (1 x 3 months)

2015

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3500

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$

LCM Paliperidone Franchise

Invega Total

Invega Oral

Invega Injectable

Paliperidone is active component of risperidone Invega ER utilizes OROSTM technology Sustenna/Trinza utilize NanoCrystalTM Technology

LCM Case Study: Risperidone Product Approval

(US)

Risperdal Oral Tablet

1993

Risperdal Oral Solution

1996

Risperdal M-Tab ODT

2003

Risperdal Consta Injectable

2003

Invega ER Oral Tablet

2006

Invega Sustenna Injectable

2009

Invega Trinza Injectable

2015

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LCM Risperidone Franchise

Franchise Total

Risperdal Total

Invega Total

Janssen: Risperdal/Invega Franchise

Risperdal Tablet 1993 Risperdal M-Tab 2003 Risperdal Oral Solution 1996 Risperdal Consta 2003

Invega ER 2006

Invega Sustenna 2009 Invega Trinza 2015

Injectable High Concentration/Viscosity

• Concentration/dose of injectable biologics (e.g. Mabs) is increasing resulting in need to deliver viscous/concentration solutions and suspensions.

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<50 mg 50-100 mg 100-250 mg 250-500 mg >500 mg

Non-Cancer

Cancer

1047 Mabs from Phase 1 to Market

Notable Approvals: 2014 Product Notable

HyQvia Injection Solution (immunoglobulin G)

A novel formulation approach incorporating a proprietary enzyme to digest hyaluronic acid and permit a product normally administered by slow IV infusion to be delivered SC. Can be administered at home with portable infusion pumps. Other products approved with Halozyme’s Enhanze technology (Rituxan, Hercpetin).

Neulasta OnPro (empegfilgrastim)

The dose is administered over an extended period for improved tolerability. Compliance and convenience is also improved. Wearable/On body injector space very active.

Notable Approvals: 2014

Product Notable

Plegridy (peginterferon beta-1a)

More oral treatments available for MS. Moves to dosing every 2 weeks. Available in patient friendly PFS and pen formats.

Alprolix (eftrenonacog alfa)

Protein-immunoglobulin fusions represent a next generation prodrug approach that blurs the line between protein engineering and traditional formulation.


Product Notable

Bydureon Dual (exenatide)

Bydureon Dual provides incremental injectable delivery format/device convenience improvements that should translate into better compliance and therapeutic outcomes. New improved device approved in 2017.

Evzio (naloxone)

Effectively a multimedia delivery device, Evzio provides printed and audio dosing instructions to allow untrained individuals to quickly and effectively administer the dose. Reportedly easier to administer without training than nasal Narcan. Good press coverage but not necessarily translating into sales.


Xultophy Pen (insulin degludec, liraglutide)

Combination product incorporates the latest generation Novo Nordisk dose-adjustable prefilled insulin syringe system providing easier use and greater accuracy. 1 X day dosing.

Trulicity Pen (dulaglutide)

Fc fused proteins in a patient friendly injection system intended to provide an extended duration of action (1 X week dosing) while encouraging patient compliance.


Copaxone Concentrated (glatiramer acetate)

A simple lifecycle management high-dose formulation that enhances convenience and promises to extend the commercial prospects of the Copaxone franchise.

Eloctate (efmoroctocog alfa)

An Fc fusion protein for the treatment of hemophilia permitting an extended dosing interval of every four days for prophylaxis.


Adynovate (rurioctocog alfa pegol)

PEG enabled product with twice weekly dosing versus 3-5 times a week.

Onivyde (irinotecan hydrochloride)

Formulation may realize promise of liposomes and irinotecan in a challenging indication.


Invega Trinza (paliperidone palmitate)

Logical lifecycle follow-on three month IM NanoCrystal formulation to complement oral Invega ER Tablets (2006)

and Invega Sustenna (2009) one month IM products for treatment of schizophrenia

Aristada (aripiprazole lauroxil)

Prodrug approach to provide extended circulating levels of well known drug aripiprazole. Dosing once every 4, 6, 8 weeks. Aristada Initio with NanoCrystalTM

technology approved 2018 provides alternative regimen to initiate patients onto any dose of ARISTADA.


Product Notable

Duodopa (levodopa, carbidopa)

Infuses a gel of levodopa/carbidopa into the jejenum via a percutaneous endoscopic gastrostomy with an outer transabdominal tube and an inner intestinal tube. $430 million sales in 2018.

Repatha (evolocumab)

Autoinjector and PFS solutions for high cholesterol management. Multi-device approval and launch. Wearable injector approved 2016.


Praluent (alirocumab)

In same space as Repatha but with a single injection once every two weeks. Multi-device approval (PFS, Pen/Autoinjector). New device to deliver 300 mg dose, 1X monthly in one injection in Phase 3.

Toujeo SOLOSTAR (insulin glargine)

Successor to Lantus SOLOSTAR. Offers better night time hypoglycemia control with lower volume of injection. Lifecycle enhancement product that brings additional patient benefits.


Product Notable

Strimvelis (Europe)

CD 34+ cells transfected with the ADA gene. Approach promises long term, possibly life long treatment and suggests opportunities in other genetic diseases currently treated with replacement protein therapies. Issue is very high $$$.

Sustol (granisetron)

Other anti-emetics have a duration of action up to 48 hours. Sustol depot offers 5 days of protection.


Zalmoxis (Europe) Adjunctive therapy to stem cell transplantation represents one of the future directions for drug delivery, the incorporation of a cellular “factory” in transplanted cells

Repatha SmartDose (evolocumab)

Third device in franchise. Wearable/On Body injector provides much more convenient dosing for large volume injection (3.5 mL)


Luxturna (voretigene neparvovec)

It seems to be an ideal indication for early gene therapy to explore; a clear mechanism of action, localized condition and one time therapy. Limited potential for life threatening adverse event.

Zilretta (triamcinolone acetonide)

Logical therapeutic option for intra-articular injection of corticosteroids. PLGA based technology provides 4 fold extension of half-life.


Sublocade (buprenorphine)

Faced with branded and generic competitors to their sublingual buprenorphine franchise, Indivor has added a long action depot formulation (up to six months) in PFS with safety needle. Analysts project sales reaching $800 million by 2023.

Oncaspar (pegaspargase)

Oncapsar has been mainstay of pediatric ALL treatment for almost 3 decades. More stable lyophilized formulation will reduce availability issues seen with other formulations.


Enbrel Mini Cartridge (etanercept)

Designed as follow on to PFS and Pen presentations. The new single use injector is intended to ensure more consistent dosing by limiting the potential points of patient confusion.

Bydureon Bcise (exenatide)

The new autoinjector provides significant patient-use improvements over previous dual chamber injector. Diabetes device space is very competitive Once a week dosing is not enough without easy-to-use device.


Ozempic (semaglutide)

Once/twice weekly dosing in FlexTouch injection pen. Potential for additional oral therapy of semaglutide as well (Phase 3)

Vyxeos (daunorubicin, cytarabine)

Combination liposome that provides molar ratios of drugs in a synergistic fashion. Analyst sales projection of $300 million by 2022.


Yescarta (axicabtagene ciloleucel)

Patient T-cells are transected ex-vivo with a retroviral construct coding the specific CD-19 targeted antigen. Analyst sales projection of $2 billion by 2022.

Kymriah (tisagenlecleucel)

CART-T immunotherapy from Novartis. Analyst sales projection of $1 billion by 2022 mostly in Europe


Onpattro (patisiran)

First commercialized RNAi therapy. 2021 sales projected to be $1.1 billion.

Dexycu (dexamethasone)

Single administration (intracameral/intraocular injection) of a corticosteroid post cataract surgery eliminates non-compliance


Lumoxiti (moxetumomab pasudotox-tdfk)

CD22-directed immuno/cytotoxin ADC. First-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukemia (HCL)

Xyosted (testosterone enantate)

Once weekly male testosterone treatment in an easy to use device.


Buvidal (buprenorphine)

First long acting treatment for opioid dependence approved in EU. Launched in January 2019 as once weekly and once monthly. Tentative US approval in December 2018 (Brixadi). Liquid lipid formulation.

Perseris (risperidone)

Once a month delivery of well established schizophrenic drug risperidone. Atrigel PLGA technology. Peak net revenues expected to be $200 to $300 million.

Notable Approvals: 2018 Other Notables

Multiple Device Based Novo FlexPen insulins Tegsedi PFS (inotersen sodium)

Actemra Auto-Injector (tocilizumab) Xolair PFS (omalizumab)

Makena SC Auto-injector (7 alpha-hydroxyprogesterone caproate)

Emgality PFS/Autoinjector (galcanezumab-gnlm) Toujeo Max SoloSTAR (insulin glargine)

Aimovig PFS/Autoinjector (erenumab-aooe)

Biosimilar Devices Fulphila PFS (pegfilgristam-jmdb)

Hyrimoz PFS/Pen (adalimumab-adaz)

Udencya PFS (pegfilgrastim-cbqv)

Nivestym PFS (filgrastim-aafi)

Ilumya PFS (tildrakizumab-asmn)

Notable Approvals: 2018 Other Notables

Multiple Peg

Jivi (damoctocog alfa pegol)

Revcovi (elapegademase-lvlr)

Palynziq PFS (pegvaliase-pqpz)

Multiple Depot Perseris (risperidone)

Buvidal (buprenorphine)

Aristada Initio (aripiprazole lauroxil) Note: All supplied in PFS

Innovative Pipeline: Injectables Program Technology Innovation

Adocia Pramlintide Insulin Combo

BioChaperone® technology enables the solubilization and stabilization of pramlintide in a ready-to-use co-formulation with insulin. Positive first clinical results reported in September 2018.

(Image Source : Adocia Website)

PharmaCyte ifosfamide

Cell-in-a-Box® is a cellulose base technology that encapsulates genetically modified cells that covert cancer drug (e.g. ifosfamide) at local site (e.g. pancreas) which reduces dose/toxicity. In Phase 2 for Pancreatic Cancer. Also planned to be used to produce insulin (Pre Clinical).

(Image Source : PharmaCyte Website)

Beta Bionics Ilet Bionic Pancreas

Pocket-size fully integrated wearable system that autonomously measure glucose levels every five min and then releases the needed insulin and/or glucagon automatically. The iLet learns over time from its performance and can change its dosing if blood sugars are running consistently high or low. In home clinical trials started July 2018. Additional trial January 2019

(Image Source : Beta Bionics Website)

Drug Delivery Technologies

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3500

Technology Count by DD Category

Injectable Targeted

39%

Injection Systems

31%

Conjugates 14%

Depot 10%

Conc/Viscous 4%

Injectable Water Insoluble

2%

Absorption Enhancers

<1%

Injectable DD Technologies

Drug Delivery Deals

Injection 41%

Oral 17%

Skin 12%

Other 11%

Transmucosal 9%

Inhalation 6%

Ophthalmic 4%

Otic <1%

Drug Delivery Related Deals 2010-2018

Injection 46%

Oral 13%

Skin 7%

Other 18%

Transmucosal 6%

Inhalation 6% Ophthalmic

4%

Otic <1%

Drug Delivery Technology Deals 2010-2018

Injectable Drug Delivery Deals

Injectable Targeted

42%

Conjugates 21%

Injection Systems

16%

Injectable Depot

8%

Other 6%

Conc/Viscous 3%

Injectable Water Insoluble

3%


1%

Injectable Drug Delivery Related Deals 2010-2018

Injectable Targeted

44%

Conjugates 19%

Injection Systems

19%

Injectable Depot

8%

Other 1%

Conc/Viscous 6% Injectable

Water Insoluble

2%


1%

Injectable DD Technology Deals 2010-2018

DD Venture Capital Funding Since 2010

Injection 45%

Oral 29%

Skin 8%

Ophthalmic 4%

Other 5% Inhalation

3%

Transmucosal 3%

Medical Devices

3%

Venture Capital Funding by DD Category

USA 74%

UK 6%

Germany 3%

France 2% Switzerland

2%

Canada 2%

China 2%

Israel 1%

Netherlands 1%

Belgium 1%

Europe, Other

4%

Japan, Asia,

Oceania 2%

Venture Capital Funding By Region

Closing Observations/Comments

• Drug Delivery Applied Across Products/Pipeline – ~40% apply DD technology (> trend)

• Injectables becoming majority of pipeline/focus – Injection based devices and delivery of biologics

• Needs Based Approach to DD Technology/Product Development – Right technology/route for right product

– Opportunities exist outside biologics!!!

Acknowledgements

• PharmaCircle Drug Delivery Team – Tugrul Kararli, PhD, MBA

– Esay Okutgen, PhD

– Guniz Iskender, PhD

– Omer Sarioglu, PhD

– Selda Candan, MS

parenteral drug delivery market trends...(irinotecan hydrochloride) formulation may realize promise...

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